Beta adrenergic receptors, or β-adrenoceptors, are sites on effector tissues or organs that are innervated by post-ganglionic adrenergic fibers of the sympathetic nervous system. The β-adrenoceptors are subclassified in β1-, β2- and β3-adrenoceptors. In general, stimulation of β1-adrenoceptors in the heart causes an increase in heart rate and cardiac contractility, whereas stimulation of β2-adrenoceptors in the smooth muscles of the trachea, of blood vessels and of the uterus leads to bronchodilation, vasodilation and inhibition of uterine contraction.
The β3-adrenoceptor is mainly present in adipocytes, the gall bladder and in the intestinal tract, and it can also be found in the brain, liver, stomach and prostate. Stimulation of these receptors leads to an increase in lipolysis and glucose uptake, inhibition of intestinal motility and anti-depression and anti-anxiety.
Moreover, it has recently been reported that the β3-adrenoceptor is the predominant β-adrenoceptor in the human bladder and that the human bladder is relaxed by β3-adrenoceptor stimulation.
In consequence, it has been found that β3-adrenoceptor stimulating agents are useful for the treatment or prevention of obesity, hyperglycemia, diseases caused by intestinal hypermobility, diseases caused by hypermobility of the biliary tract or by biliary calculi, depression and anxiety, overactive bladder and urinary incontinence, and so on. Efforts are ongoing to develop β3-adrenoceptor stimulating agents for the to treatment or prevention of such diseases but currently no such agent has been marketed yet.
Therefore, it has been desired to develop novel agents with activity at the β3-adrenoceptor and especially with a stimulating effect at this receptor.
Compounds of the 1-aryloxy-2-propanol-3-amine scaffold, in the following simply named aryloxypropanolamine, have been reported as agonists of the β3-adrenoceptor (WO02006221, WO02006230, WO02006235, WO02006255, WO02006258, WO-0100726, WO01036411, WO01017989, WO01044227, WO02094820, WO02006276, WO02038544, WO03024948, WO99051564, WO98041497, WO98037056, WO95004047, WO98022480, WO98007445, U.S. Pat. No. 5,480,908, US20050222247, U.S. Pat. No. 5,451,677, UA20030040530, FR02780057) and also as antagonists of the tachykinin receptor NK1 (WO04014850). The preparation of a certain β3-receptor construct can be deduced from WO90008775. β3-adrenoceptor agonists were also combined with alpha-adrenoceptor and/or 5-alpha reductase inhibitors, with a serotonin and/or norepinephrine reuptake inhibitor or an agent intervening in the prostaglandin metabolism for treatment of bladder dysfunction (US20050101607, WO05042021, WO04047830, WO05060955).
For an overview of aryloxypropanolamines as β3-ligands, see also M. Sawa et al., Curr. Med. Chem. 2006, 13, 25.
It has now been found that certain novel aryloxypropanolamines are effective as β3-adrenoceptor agonists and are useful in the treatment of medical conditions mediated by β3-adrenoceptors.
According to the present invention compounds are provided having the formula I
and the pharmaceutically acceptable salt or solvate thereof,whereinQ is a pyrimidinyl or dihydropyrimidinyl residue that may be unsubstituted or substituted with one or more residues R13, R14, or R15, or Q is a pyrimidin-4-yl or dihydropyrimidin-4-yl ring which is substituted with a group R8 and which may be anellated in the 5,6-position of the pyrimidin-4-yl or dihydropyrimidin-4-yl ring (resulting in a new ringsystem that is anellated in the 2,3-position according to IUPAC) to a five-membered heterocycle, preferably selected from among thiophenyl, furanyl and pyrollyl, which 5-membered heterocycle may be unsubstituted or substituted with one or two substituents selected from R9, R10, R11 or R12;
A person skilled in the art would understand a thiophenyl to be a 5-membered heteroaromatic ring with a sulphur incorporated, also described as thienyl, which might, if not anellated, also be named thiophen-2-yl or thiophen-3-yl being the same as 2-thienyl and 3-thienyl, respectively.
In another embodiment of the invention, Q is a pyrimidinyl or dihydropyrimidinyl residue that might be unsubstituted or substituted with one or more residues R13, R14, or R15, or Q is a pyrimidin-4-yl or dihydropyrimidin-4-yl ring which is substituted with a group R8 and which may be anellated in the 5,6-position of the pyrimidin-4-yl or dihydropyrimidin-4-yl ring (resulting in a new ringsystem that is anellated in the 2,3-position according to IUPAC) to a five-membered heterocycle, preferably thiophenyl, which might be unsubstituted or substituted with one or two substituents selected from R9, R10, R11 or R12;
R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkenyl, alkinyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, dialkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl, alkylaminosulfonyl, and dialkylaminosulfonyl wherein each alkyl, alkenyl or alkinyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, fluoro, and NR6R7; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR6R7, cyano and nitro; provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;
In another embodiment of the invention, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkenyl, alkinyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl; provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;
R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkenyl, alkinyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, wherein each alkyl, alkenyl or alkinyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, fluoro, and NR6R7;
In another embodiment of the invention, R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkenyl, alkinyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl;
R4 is hydrogen, alkylcarbonyl, or alkyl;
R5 is selected from hydrogen, alkyl, wherein alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, fluoro, and NR6R7;
R6 and R7 are independently selected from hydrogen, alkyl, aryl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylcarbonyl, and heteroarylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR16R17, cyano and nitro;R8 is selected from among hydrogen, alkyl, hydroxyl, alkoxy;R9, R10, R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, fluoro, NR6R7, and carboxy, and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among alkyl, hydroxyl, alkoxy, alkylthio, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, carboxymethoxy, alkoxy-carbonylalkoxy, halogen, carboxy, carbamoyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, sulfo, alkylsulfinyl, NR6R7, cyano and nitro, wherein two of these residues might form a 5-7 membered non-aromatic ring.
Alternatively, R9, R10, R11 and R12 are defined as above wherein each mono- or bicyclic aromatic or heteroaromatic ring can additionally be substituted with one or more carboxyalkoxy residues;
In another embodiment of the invention, R9, R10, R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring;
R13, R14 and R15 are independently selected from hydrogen, alkyl, carboxy, NR6R7, aryl, heteroaryl, hydroxyl, alkoxy, alkoxycarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, halogen and nitro, wherein each alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, fluoro and aryl; and wherein two of these residues (selected from R13, R14, R15) might form a 5-7 membered non-aromatic or aromatic ring;and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy, halogen, carboxy, alkoxycarbonyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.
R16 and R17 are independently selected from among hydrogen, C1-C8 alkyl, phenyl, thiophenyl, pyridyl C1-C8 alkylsulfonyl, phenylsulfonyl, thiophenylsulfonyl, pyridylsulfonyl C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, thiophenylcarbonyl, pyridylcarbonyl, and phenylcarbonyl and wherein R16 and R17 may form a 5-7 membered cycle.
In the context of the present invention, an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-alkyl, preferably a linear or branched chain of one to six carbon atoms; an alkenyl group, if not stated otherwise, denotes a linear or branched C2-C6-alkenyl; and an alkinyl group, if not stated otherwise, denotes a linear or branched C2-C6-alkinyl group, which may be substituted by one or more substituents R′.
To keep the definitions as short as possible, in the following paragraphs “alkyl” is to be understood to encompass alkyl, alkenyl and alkinyl.
In another embodiment of the invention, an alkyl group, if not stated otherwise, denotes a linear or branched C1-C12 alkyl, C2-C6-alkenyl and C2-C6-alkinyl group, which may be substituted by one or more substituents R′.
In another embodiment of the invention, in the context of the present invention, an alkyl group, if not stated otherwise, denotes a linear or branched C1-C6-alkyl and preferably a C1-C3 alkyl; C2-C6-alkenyl and C2-C6-alkinyl group, which might be optionally substituted by one or more substituents R′.
The C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkinyl residue may be selected from the group consisting of —CH3, —C2H5, —CH═CH2, —C≡CH, —C3H7, —CH(CH3)2, —CH2—CH═CH2, —C(CH3)—CH2, —CH═CH—CH3, —C≡C—CH3, —CH2—C≡CH, —C4H9, —CH2—CH(CH3)2, —CH(CH3)—C2H5, —C(CH3)3, —C5H11, —C6H13, —C(R′)3, —C2(R′)5, —CH2—C(R′)3, —C3(R′)7, —C2H4—C(R′)3, —C2H4—CH═CH2, —CH═CH—C2H5, —CH═C(CH3)2, —CH2—CH═CH—CH3, —CH═CH—CH═CH2, —C2H4—C≡CH, —C≡C—C2H5, —CH2—C≡C—CH3, —C≡C—CH═CH2, —CH═CH—C≡CH, —C≡C—C≡CH, —C2H4—CH(CH3)2, —CH(CH3)—C3H7, —CH2—CH(CH3)—C2H5, —CH(CH3)—CH(CH3)2, —C(CH3)2—C2H5, —CH2—C(CH3)3, —C3H6—CH═CH2, —CH═CH—C3H7, —C2H4—CH═CH—CH3, —CH2—CH═CH—C2H5, —CH2—CH═CH—CH═CH2, —CH═CH—CH═CH—CH3, —CH═CH—CH2—CH═CH2, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —CH2—CH═C(CH3)2, —C(CH3)═C(CH3)2, —C3H6—C≡CH, —C≡C—C3H7, —C2H4—C≡C—CH3, —CH2—C≡C—C2H5, —CH2—C═C—CH═CH2, —CH2—CH═CH—C≡CH, —CH2—C≡C—C≡CH, —C≡C—CH═CH—CH3, —CH═CH—C≡C—CH3, —C≡C—C≡C—CH3, —C≡C—CH2—CH═CH2, —CH═CH—CH2—C≡CH, —C≡C—CH2—C≡CH, —C(CH3)═CH—CH═CH2, —CH═C(CH3)—CH═CH2, —CH═CH—C(CH3)═CH2, —C(CH3)═CH—C≡CH, —CH═C(CH3)—C≡CH, —C≡C—C(CH3)—CH2, —C3H6—CH(CH3)2, —C2H4—CH(CH3)—C2H5, —CH(CH3)—C4H9, —CH2—CH(CH3)—C3H7, —CH(CH3)—CH2—CH(CH3)2, —CH(CH3)—CH(CH3)—C2H5, —CH2—CH(CH3)—CH(CH3)2, —CH2—C(CH3)2—C2H5, —C(CH3)2—C3H7, —C(CH3)2—CH(CH3)2, —C2H4—C(CH3)3, —CH(CH3)—C(CH3)3, —C4H8—CH═CH2, —CH═CH—C4H9, —C3H6—CH═CH—CH3, —CH2—CH═CH—C3H7, C2H4—CH═CH—C2H5, —CH2—C(CH3)═C(CH3)2, —C2H4—CH═C(CH3)2, —C4H8—C≡CH, —C≡C—C4H9, —C3H6—C≡C—CH3, —CH2—C≡C—C3H7, and —C2H4—C≡C—C2H5;
R′ independently represents H, —CO2R″, —CONHR″, —CR″O, —SO2NHR″, —NR″-CO-haloalkyl, —NO2, —NR″—SO2-haloalkyl, —NR″-SO2-alkyl, —SO2-alkyl, —NR″-CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl or heteroaryl;R″ independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
In another embodiment of the invention, R′ independently represents H, —CO2R″, —CONR″R′″, —CR″O, —SO2NR″R′″, —NR″-CO-haloalkyl, —NO2, —NR″-SO2-haloalkyl, —NR″-SO2-alkyl, —NR″-SO2-aryl, —NR″-SO2-heteroaryl, —SO2-alkyl, —SO2-aryl, —SO2-heteroaryl, —SO-alkyl, NR″-CO-alkyl, —NR″-CO-aryl, —NR″-CO-heteroaryl, —NR″—CO—NR″′Riv, —CN, alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkoxy, aryl, arylalkyl, heteroaryl, aryloxy or heteroaryloxy; wherein two R′ can form ═O;
in this other embodiment of the invention, R″, R′″, Riv independently represent H, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl;
a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably four to eight carbon atoms, wherein one or more of the carbon atoms in the ring may be substituted by a group E, E being O, S, SO, SO2, N, or NR″, R″ being as defined above; the C3-C8-cycloalkyl residue may be selected from the group consisting of -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-C8H15, morpholine-4-yl, piperidinyl, piperazinyl, and 1-alkylpiperazine-4-yl;a heterocyclyl group denotes a 3 to 8-membered heterocyclic non-aromatic group which contains at least one heteroatom selected from O, N, and S, wherein the heterocyclyl group may be fused to another non-aromatic ring and may be substituted by one or more substituents R′, wherein R′ is as defined above;
A person skilled in the art would understand that in the context of this invention, heterocyclyl might be a representative of cycloalkyl as defined above;
In another embodiment of the invention, a cycloalkyl group denotes a non-aromatic ring system containing three to eight carbon atoms, preferably five to seven carbon atoms, which might be optionally substituted by one or more substituents R′, and wherein one or more of the carbon atoms in the ring may be replaced by a group E, E being O, S, SO, SO2, N, or NR″, R′ and R″ being as defined above; the C3-C8-cycloalkyl residue might be selected from the group consisting of -cyclo-C3H5, -cyclo-C4H7, -cyclo-C5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-C8H15, morpholine-4-yl, piperidinyl, piperazinyl, and 1-alkylpiperazine-4-yl;
an alkoxy group denotes an O-alkyl group, the alkyl group being as defined above; the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;
alternatively, an alkoxy group is defined as above but might likewise preferably be abenzyloxy group;
an alkylthio group denotes a S-alkyl group, the alkyl group being as defined above;
a haloalkyl group denotes an alkyl group which is substituted by one to five halogen atoms, the alkyl group being as defined above; the haloalkyl group is preferably a —C(R18)3, —CR18(R18′)2, —CR18(R18)R18″, —C2(R18)5, —CH2—C(R18)3, —CH2—CR18(R18′)2, —CH2—CR18(R18′)R18″, —C3(R18)7, or —C2H4—C(R18)3, wherein R18, R18′, R18″ represent F, Cl, Br or I, preferably F;alternatively, a haloalkyl group denotes an alkyl group which is substituted by one to seven halogen atoms, which is preferably chosen as defined above but might also represent —CH(R18)2;a hydroxyalkyl group denotes a HO-alkyl group, the alkyl group being as defined above;
a haloalkoxy group denotes an alkoxy group which is substituted by one to seven halogen atoms, the alkyl group being as defined above; the haloalkoxy group is preferably a —OC(R18)3, —OCR18(R18′)2, —OCR18(R18′)R18″, —OC2(R18)5, —OCH2—C(R18)3, —OCH2—CR18(R18′)2, —OCH2—CR18(R18′)R18″, —OC3(R18)7, —OC2H4—C(R18)3, wherein R18, R18′, R18″ represent F, Cl, Br or I, preferably F;
alternatively, a haloalkoxyl group denotes an alkoxyl group which is substituted by one to seven halogen atoms, which is preferably chosen as defined above but might also represent —OCH(R18)2, OC2H4(R18), —OC2(R18), OC2(R18)3, —OC(R18)=C(R18)-, or —OCH═C(R18)-;a hydroxyalkylamino group denotes a (HO-alkyl)2-N— group or HO-alkyl-NH— group, the alkyl group being as defined above;an alkylamino group denotes a HN-alkyl or N-dialkyl group, the alkyl group being as defined above;
Alternatively, an alkylamino group denotes a HN-alkyl or N-dialkyl group, the alkyl group being as defined above and might be defined independently from each other;
a halogen group is fluorine, chlorine, bromine, or iodine;
an aryl group denotes an aromatic group having five to fifteen carbon atoms, which may be substituted by one or more substituents R′, and may be fused to another aromatic ring, where R′ is as defined above; the aryl group is preferably a phenyl group, -o-C6H4—R′, -m-C6H4—R′, -p-C6H4—R′, 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;
In another embodiment of the invention, an aryl group denotes an aromatic group having five to fifteen carbon atoms, preferably having five to ten carbon atoms, which might be optionally substituted by one or more substituents R′, and might be fused to another aromatic ring, where R′ is as defined above; the aryl group is preferably a phenyl group, -o-C6H4—R′, -m-C6H4—R′, -p-C6H4—R′, —C6H3R′2, —C6H2R′3, 1-naphthyl or 2-naphthyl, R′ groups might be defined independently from each other; R′ groups might form a 5-7 membered non-aromatic ring;
a heteroaryl group denotes a 5- or 6-membered heterocyclic group which contains at least one heteroatom like O, N, S. This heterocyclic group can be fused to another aromatic ring. For example, this group can be selected from a thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, benzooxazol-2-yl, benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl, benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl, benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl pyrid-6-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazaindene, isothiazolopyrazine, 6-pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benz-imidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine, isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, or triazolopyridazine group. This heterocyclic group may be substituted by one or more substituents R′, wherein R′ is as defined above;
The compositions might take suitable forms for oral administration such as solid dosage forms (e.g. tablets, pills, capsules, granulates, pellets, powders, multi-particulate formulations such as beads, granules or crystals and dragees) or oral liquid forms (e.g. solutions, droplets syrups, emulsions, suspensions).
The compositions described herein can be administered transdermally, e.g. in the form of transdermal therapeutic systems (e.g. patches) or topical formulations (e.g. powder, liposomes, crèmes, ointment, lotion, gels, dispersion, suspension, spray, solution). Topical formulations can also be administered via the buccal, vaginal, ocular, pulmonary or nasal route.
The compositions might take suitable sterile forms for parenteral administration (for instance intravenous, intramuscular or subcutaneous application) such as solutions, suspension, dispersion of colloidal drug carriers, or lyophilized form of the above mentioned sterile lipid forms for re-constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
The compositions described herein can also be administered rectal or vaginal as semisolid therapeutic systems (e.g. ovula or suppository).
“Pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government or being listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. These salts are selected but not limited to the group consisting of acetate, 2,2-dichloroacetate, tert-butylacetate, trimethylacetate, adipate, alginate, ascorbate, aspartate, benzoate, 3-(4-hydroxybenzoyl)benzoate, benzenesulfonate, 4-chlorobenzenesulfonate, 2-acetamidobenzoate, caproate, caprate, camphorate, camphorsulfonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, laurylsulfate, edisilate, esylate or ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, isetionate, formate, fumarate, galactarate, gentisate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, oxoglutarate, glycolate, hexanoate, hippurate, bromide or hydrobromide, chloride or hydrochloride, hydroxynaphthoate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylate, muconate, napsilate or naphthalene-2-sulfonate, napadisilate, xinafoate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pyruvate, embonate, phosphate, hydrogenphosphate or dihydrogenphosphate, pidolate, propionate, 3-phenylpropionate, salicilate, p-aminosalicylate, sebacate, stearate, succinate, sulfate or hydrogensulfate, tannate, tartrate, rhodanide, tosylate, undecylenate, ammonia, arginine, benethamine, benzathine, calcium, choline, deanol, diethanolamine, diethylammonium, ethanolamine, ethylendiamine, meglumine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine or zinc [Handbook of Pharmaceutical Salts, Ed. P. H. Stahl, C. G. Wermuth, Zurich 2002].
The term “salt” as used in the present application is meant to encompass crystalline as well as amorphous forms. It is clear to the skilled artisan that various polymorphs of a given salt can exist. The term “salt” in this application encompasses the particular polymorphs as well as mixtures of various polymorphs.
The term “solvate” hereby includes stoichiometric as well as non-stoichiometric inclusions of solvents such as e.g. ethanol or isobutylacetate into the crystal structure. The term “solvate” also includes hydrates wherein water is included in the crystal structure.    According to the present invention compounds are preferred according to formula I, wherein
                wherein the dotted bond represents a single or a double bond;        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, phenylsulfonylaminomethyl, thiophenylsulfonylaminomethyl, alkylaminosulfonyl, and dialkylaminosulfonyl, wherein each alkyl, alkenyl or alkinyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7; and wherein each phenyl or thiophenyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        In another preferred embodiment, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, to phenylsulfonylaminomethyl, thiophenylsulfonylaminomethyl and C1-C6 alkylaminosulfonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7; and wherein each phenyl or thiophenyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, and C1-C6 alkoxycarbonyl, wherein each alkyl, alkenyl or alkinyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7;        R4 is hydrogen, C1-C3 alkylcarbonyl, or C1-C3 alkyl;        R5 is selected from hydrogen, C1-C3 alkyl, which might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thiophenylsulfonyl, C1-C8 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, phenylcarbonyl, and thiophenylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each phenyl or thiophenyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR16R17, cyano and nitro;        R8 is selected from hydrogen, methyl, hydroxyl, and methoxy;        R9, R10, R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thiophenyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, or a bicyclic aromatic or heteroaromatic ring selected from quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzothiazolyl and naphthalyl wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy; and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxymethoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, di(C1-C4)alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring;        Alternatively, R9, R10, R11 and R12 are defined as above wherein each mono- or bicyclic aromatic or heteroaromatic ring can additionally be substituted with one or more carboxy(C1-C4)alkoxy residues;        R13, R14 and R15 are independently selected from hydrogen, C1-C4 alkyl, carboxy, NR6R7, phenyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, phenylaminocarbonyl, thiophenylaminocarbonyl, halogen and nitro, wherein each alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C4 alkoxy, fluoro and phenyl; wherein two of these residues selected from R13, R14 and R15 might form a 5-7 membered non-aromatic or aromatic ring;        and wherein phenyl or thiophenyl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C4 alkoxy, halogen, carboxy, C1-C4 alkoxycarbonyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        Alternatively, R13, R14 and R15 are defined as above and can additionally be selected from C1-C3 haloalkyl;        R16 and R17 are independently selected from among hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkylsulfonyl, phenylsulfonyl, thiophenylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, phenylcarbonyl, and thiophenylcarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Especially preferred are compounds according to formula I, wherein
                wherein the dotted bond represents a single or a double bond;        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, cyano, nitro, sulfamoyl, NR6R7, C1-C3 alkyl, C2-C3 alkenyl, ethinyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, morpholinocarbonyl, thiophen-2-ylsulfonylaminomethyl, wherein each alkyl or alkenyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7; and wherein the thiophenyl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        In another especially preferred embodiment, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, cyano, nitro, sulfamoyl, NR6R7, C1-C3 alkyl, C2-C3 alkenyl, ethinyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, morpholinocarbonyl, thiophen-2-ylsulfonylaminomethyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7; and wherein the thiophenyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR6R7 and cyano, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C3 alkyl, C2-C3 alkenyl, ethinyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, and C1-C3 alkoxycarbonyl, wherein each alkyl or alkenyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R4 is hydrogen or methyl;        R5 is selected from hydrogen and methyl, wherein methyl might be unsubstituted or substituted with a residue selected from among hydroxyl, methoxy, ethoxy, fluoro, and NR6R7;        Alternatively, R5 is selected from hydrogen and methyl, wherein methyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, ethoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C3 alkyl, C1-C8 alkylsulfonyl, thiophen-2-ylsulfonyl, C1-C8 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C8 alkylaminocarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkoxy preferred, C1-C3 alkoxy, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein the thiophenyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR16R17 and cyano;        R8 is selected from hydrogen and methyl;        R9, R10, R11 and R12 are independently selected from hydrogen, NR6R7, C1-C6 alkyl, phenyl, thiophenyl, pyridinyl, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, fluoro, NR6R7, and carboxy; and wherein each monocyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, carboxymethoxy, C1-C3 alkoxycarbonyl(C1-C2)alkoxy, preferably 2-alkoxy-2-oxoethoxy, halogen, carboxy, NR6R7 and cyano; wherein two of these residues might form a 5-7 membered non-aromatic ring;        Alternatively, R9, R10, R11 and R12 are defined as above and can additionally be selected from furanyl; wherein each monocyclic aromatic or heteroaromatic ring can additionally be substituted with one or more residues selected from C1-C4 alkylaminocarbonyl and carboxy(C1-C2)alkoxy;        R13, R14 and R15 are independently selected from hydrogen, C1-C3 alkyl, carboxy, NR6R7, phenyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, phenylaminocarbonyl, halogen and nitro, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, fluoro and phenyl; and wherein phenyl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, carboxy, C1-C3 alkoxycarbonyl, NR6R7 and cyano; wherein two of these residues might form a 5-7 membered non-aromatic ring.        Alternatively, R13, R14 and R15 are defined as above and can additionally be selected from CF3;        R16 and R17 are independently selected from among hydrogen, C1-C3 alkyl, C1-C4 alkylsulfonyl, thiophen-2-ylsulfonyl, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C4 alkylaminocarbonyl wherein R16 and R17 may form a 5-7 membered cycle.        
Another preferred embodiment according to the present invention are compounds according to formula I, wherein                R1 is selected from hydrogen, hydroxyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, carboxy, and methoxymethyl;        R2 is selected from hydrogen, hydroxyl, methoxycarbonyl, and hydroxymethyl;        R3 is selected from hydrogen, methyl, ethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, hydroxymethyl;        R4 is hydrogen or methyl;        R5 is hydrogen or methy;        R8 is hydrogen or methyl;        R9, if present, is hydrogen, methyl, unsubstituted phenyl, halophenyl, preferably para-fluoro phenyl, or thiophenyl;        R10, if present, is hydrogen, methyl, unsubstituted phenyl, or halophenyl;        R11 and R12, if present, are both hydrogen;        R13, R14 and R15, if present, are independently selected from hydrogen and methyl.        
Another preferred embodiment according to the present invention are compounds according to formula I, wherein                the dotted bond represents a single or a double bond; and wherein        R1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, carboxy, and methoxymethyl;        R2 is selected from hydrogen, hydroxyl, methoxycarbonyl, carboxy, and hydroxymethyl;        R3 is selected from hydrogen, halogen, methyl, ethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, hydroxymethyl;        R4 is hydrogen or methyl;        R5 is hydrogen or methyl;        R8 is hydrogen or methyl;        R9, if present, is hydrogen, methyl, unsubstituted phenyl, halophenyl, preferably para-fluorophenyl, or thiophenyl;        R10, if present, is hydrogen, methyl, unsubstituted phenyl, or halophenyl;        R11 and R12, if present, are both hydrogen;        R13, R14 and R15, if present, are independently selected from hydrogen and methyl.        
According to the present invention compounds according to formula I are preferred, or the pharmaceutically acceptable salt or solvate thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, and having the formula II
                wherein R1, R2, R3, R4, R5, R8, R9 and R10 are as defined as above for formula I.        
Another preferred embodiment of the present invention encompass the above described compounds whereas                R9 is hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thiophenyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, or a bicyclic aromatic or heteroaromatic ring selected from quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzothiazolyl and naphthalyl, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy; and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxymethoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, di(C1-C4)alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring; and        R10 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, or fluoro;        
Another preferred embodiment of the present invention are compounds according to formula II, wherein                R9 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, or fluoro;        and        R10 is hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thiophenyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, or a bicyclic aromatic or heteroaromatic ring selected from quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzothiazolyl and naphthalyl, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy; and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxymethoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, di(C1-C4)alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        
Another preferred embodiment of the present invention are compounds according to formula II,                wherein the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        In another embodiment of the invention, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, wherein each alkyl, may be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR6R7, cyano and nitro; provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl;        In another embodiment of the invention, R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, wherein each alkyl, might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R4 is hydrogen, alkylcarbonyl, or alkyl;        R5 is selected from hydrogen, alkyl, wherein alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, alkyl, aryl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylcarbonyl, and heteroarylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR16R17, cyano and nitro;        R8 is selected from among hydrogen, alkyl, hydroxyl, alkoxy;        R9 and R10 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring,        In another embodiment of the invention, R9 and R10 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring, wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, NR6R7, and carboxy, and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues, which are preferably selected from among alkyl, hydroxyl, alkoxy, alkylthio, alkylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl, carboxyalkoxy, alkoxycarbonylalkoxy, halogen, carboxy, carbamoyl, sulfamoyl, alkylaminosulfonyl, alkylsulfonyl, sulfo, alkylsulfinyl, NR6R7, cyano and nitro, wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C8 alkyl, phenyl, thienyl, pyridyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, pyridylsulfonyl, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, thienylcarbonyl, pyridylcarbonyl, and phenylcarbonyl and wherein R16 and R17 might form a 5-7 membered cycle.        
Also preferred are compounds according to formula II, wherein                the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, phenylsulfonylaminomethyl, thienylsulfonylaminomethyl and C1-C6 alkylaminosulfonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, and C1-C6 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7;        R4 is hydrogen, C1-C3 alkylcarbonyl, or C1-C3 alkyl;        R5 is selected from hydrogen, C1-C3 alkyl, which might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR16R17, cyano and nitro;        R8 is selected from hydrogen, methyl, hydroxyl, and methoxy;        R9 and R10 are independently selected from hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thienyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl and naphthalyl;        wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy;        and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues preferably selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Especially preferred are compounds according to the present invention, wherein                R9 is hydrogen, NR6R7, C1-C3 alkyl, phenyl, thiophen-2-yl, pyridinyl, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C4 alkoxy, NR6R7, and carboxy; and wherein each monocyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, carboxymethoxy, C0-C2 alkoxycarbonyl(C1-C2)alkoxy, preferably 2-alkoxy-2-oxoethoxy, fluoro, chloro, bromo, carboxy, NR6R7, cyano and nitro; and        R10 is hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, or fluoro;        and the dotted bond represents a double bond.        
Another especially preferred embodiment of the present invention are compounds according to formula II, wherein                R9 is hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, or fluoro;        and        R10 is hydrogen, NR6R7, C1-C3 alkyl, phenyl, thiophen-2-yl, pyridinyl, wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C4 alkoxy, NR6R7, and carboxy; and wherein each monocyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, carboxymethoxy, C0-C2 alkoxycarbonyl(C1-C2)alkoxy, preferably 2-alkoxy-2-oxoethoxy, fluoro, chloro, bromo, carboxy, NR6R7, cyano and nitro and the dotted bond represents a double bond.        
Especially preferred are compounds according to formula II, wherein                the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, cyano, nitro, sulfamoyl, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, morpholinocarbonyl, 2-thienylsulfonylaminomethyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7; and wherein the thienyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR6R7 and cyano, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, and C1-C3 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R4 is hydrogen or methyl;        R5 is selected from hydrogen and methyl, wherein methyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, ethoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C3 alkyl, C1-C8 alkylsulfonyl, 2-thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C8 alkylaminocarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein the thienyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR16R17 and cyano;        R8 is selected from hydrogen and methyl;        R9 and R10 are independently selected from hydrogen, NR6R7, C1-C6 alkyl, phenyl, thienyl, furanyl, pyridinyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, NR6R7, and carboxy; and wherein each monocyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues preferably selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, carboxy(C1-C2)alkoxy, C1-C3 alkoxycarbonyl(C1-C2)alkoxy preferably 2-alkoxy-2-oxoethoxy, halogen, carboxy, NR6R7 and cyano; wherein two of these residues might form a 5-7 membered non-aromatic ring;        R16 and R17 are independently selected from among hydrogen, C1-C3 alkyl, C1-C4 alkylsulfonyl, 2-thienylsulfonyl, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C4 alkylaminocarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Another especially preferred embodiment of the present invention are compounds according to formula II, wherein                the dotted bond represents a single or a double bond; and wherein        R1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, carboxy, and methoxymethyl;        R2 is selected from hydrogen, hydroxyl, methoxycarbonyl, carboxy, and hydroxymethyl;        R3 is selected from hydrogen, halogen, methyl, ethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, hydroxymethyl;        R4 is hydrogen or methyl;        R5 is hydrogen or methyl;        R8 is hydrogen or methyl;        R9 is hydrogen, methyl, unsubstituted phenyl, halophenyl, preferably para-fluorophenyl, or thienyl;        R10 is hydrogen, methyl, unsubstituted phenyl, or halophenyl;        
Another preferred embodiment of the present invention are compounds according to formula I and the pharmaceutically acceptable salt or solvate thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, having the formula III
                wherein R1, R2, R3, R4, R5, R8, R11 and R12 are defined as above for formula I.        
Also preferred are compounds according to formula III, wherein                one of R11 and R12 is hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thiophenyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, or a bicyclic aromatic or heteroaromatic ring selected from quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzothiazolyl and naphthalyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy; and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxymethoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, di(C1-C4)alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues selected from R11 and R12 might form a 5-7 membered non-aromatic ring;        and the other one of R11 and R12 is hydrogen or C1-C6 alkyl; wherein the C1-C6 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, or fluoro.        
Another preferred embodiment of the present invention are compounds according to formula III,                wherein the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        In another embodiment of the invention, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, wherein each alkyl, may be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR6R7, cyano and nitro; provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl;        In another embodiment of the invention, R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, wherein each alkyl, might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R4 is hydrogen, alkylcarbonyl, or alkyl;        R5 is selected from hydrogen, alkyl, wherein alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, alkyl, aryl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylcarbonyl, and heteroarylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR16R17, cyano and nitro;        R8 is selected from among hydrogen, alkyl, hydroxyl, alkoxy;        R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring,        In another embodiment of the invention, R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, alkyl and a mono- or bicyclic aromatic or heteroaromatic ring, wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, NR6R7, and carboxy, and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues, which are preferably selected from among alkyl, hydroxyl, alkoxy, alkylthio, alkylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl, carboxyalkoxy, alkoxycarbonylalkoxy, halogen, carboxy, carbamoyl, sulfamoyl, alkylaminosulfonyl, alkylsulfonyl, sulfo, alkylsulfinyl, NR6R7, cyano and nitro, wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C8 alkyl, phenyl, thienyl, pyridyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, pyridylsulfonyl, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, thienylcarbonyl, pyridylcarbonyl, and phenylcarbonyl and wherein R16 and R17 might form a 5-7 membered cycle.        
Also preferred are compounds according to formula III, wherein                the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, phenylsulfonylaminomethyl, thienylsulfonylaminomethyl and C1-C6 alkylaminosulfonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, and C1-C6 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7;        R4 is hydrogen, C1-C3 alkylcarbonyl, or C1-C3 alkyl;        R5 is selected from hydrogen, C1-C3 alkyl, which might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR16R17, cyano and nitro;        R8 is selected from hydrogen, methyl, hydroxyl, and methoxy;        R11 and R12 are independently selected from hydrogen, carboxy, NR6R7, C1-C6 alkyl and a mono- or bicyclic aromatic or heteroaromatic ring selected from phenyl, furanyl, thienyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxydiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl, quinolinyl, quinoxalinyl, indolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl and naphthalyl;        wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, NR6R7, and carboxy;        and wherein each mono- or bicyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues preferably selected from among C1-C6 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylcarbonyl, C1-C6 alkylaminocarbonyl, C1-C4 alkoxycarbonyl, carboxy(C1-C4)alkoxy, C1-C4 alkoxycarbonyl(C1-C4)alkoxy, halogen, carboxy, carbamoyl, sulfamoyl, C1-C4 alkylaminosulfonyl, C1-C4 alkylsulfonyl, sulfo, C1-C4 alkylsulfinyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C6 alkyl, phenyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
An especially preferred embodiment of the present invention are compounds according to formula III, wherein                one of R11 and R12 is hydrogen, NR6R7, C1-C3 alkyl, phenyl, thiophen-2-yl, wherein alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C4 alkoxy, NR6R7, and carboxy; and wherein the phenyl or thiophen-2-yl may be unsubstituted or substituted with one or more residues selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, carboxymethoxy, C0-C2 alkoxycarbonyl(C1-C2)alkoxy, preferably 2-alkoxy-2-oxoethoxy, fluoro, chloro, bromo, carboxy, NR6R7, cyano and nitro; wherein two of these residues may form a 5-7 membered non-aromatic ring        the other one of R11 and R12 is hydrogen or C1-C3 alkyl, wherein the C1-C3 alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, or fluoro;        and the dotted bond represents a double bond.        
Also especially preferred are compounds according to formula III, wherein                the dotted bond represents a single or a double bond; and wherein        R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, cyano, nitro, sulfamoyl, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, morpholinocarbonyl, 2-thienylsulfonylaminomethyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7; and wherein the thienyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR6R7 and cyano, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C8 alkylcarbonyl, and C1-C3 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R4 is hydrogen or methyl;        R5 is selected from hydrogen and methyl, wherein methyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, ethoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C3 alkyl, C1-C8 alkylsulfonyl, 2-thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C8 alkylaminocarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein the thienyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR16R17 and cyano;        R8 is selected from hydrogen and methyl;        R11 and R12 are independently selected from hydrogen, NR6R7, C1-C6 alkyl, phenyl, thienyl, furanyl, pyridinyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, NR6R7, and carboxy; and wherein each monocyclic aromatic or heteroaromatic ring can be unsubstituted or substituted with one or more residues preferably selected from among C1-C3 alkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, carboxy(C1-C2)alkoxy, C1-C3 alkoxycarbonyl(C1-C2)alkoxy preferably 2-alkoxy-2-oxoethoxy, halogen, carboxy, NR6R7 and cyano; wherein two of these residues might form a 5-7 membered non-aromatic ring;        R16 and R17 are independently selected from among hydrogen, C1-C3 alkyl, C1-C4 alkylsulfonyl, 2-thienylsulfonyl, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C4 alkylaminocarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Another especially preferred embodiment of the present invention are compounds according to formula III, wherein                the dotted bond represents a single or a double bond; and wherein        R1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, carboxy, and methoxymethyl;        R2 is selected from hydrogen, hydroxyl, methoxycarbonyl, carboxy, and hydroxymethyl;        R3 is selected from hydrogen, halogen, methyl, ethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, hydroxymethyl;        R4 is hydrogen or methyl;        R5 is hydrogen or methyl        R8 is hydrogen or methyl;        R11 is hydrogen, methyl, unsubstituted phenyl, halophenyl, preferably para-fluorophenyl, or thienyl;        R12 is hydrogen, methyl, unsubstituted phenyl, or halophenyl;        
According to the present invention especially preferred is a compound according to formula I, or the pharmaceutically acceptable salts or solvates thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, and having the formula IV
                wherein R1, R2, R3, R4, R5, R13, R14 and R15 are defined as above for formula I.        
Especially preferred are compounds according to the present invention according to formula IV, wherein R13, R14 and R15 are selected from hydrogen and C1-C3 alkyl, which may be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, ethoxy or NR6R7.
Another preferred embodiment of the present invention encompass compounds of formula IV, wherein                R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        In another embodiment of the invention, R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, arylsulfonylaminomethyl, heteroarylsulfonylaminomethyl and alkylaminosulfonyl, wherein each alkyl, may be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR6R7 cyano and nitro; provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl;        In another embodiment of the invention, R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, alkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, wherein each alkyl, might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R4 is hydrogen, alkylcarbonyl, or alkyl;        R5 is selected from hydrogen, alkyl, wherein alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, alkyl, aryl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylcarbonyl, and heteroarylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, alkyl, carboxy, NR16R17, cyano and nitro;        R13, R14 and R11 are independently selected from hydrogen, alkyl, haloalkyl, carboxy, NR6R7, aryl, heteroaryl, hydroxyl, alkoxy, alkoxycarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, halogen and nitro, wherein each alkyl might be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, fluoro and aryl; and wherein two of these residues (selected from R13, R14, R15) might form a 5-7 membered non-aromatic or aromatic ring and wherein each aryl or heteroaryl is a monocyclic aromatic or heteroaromatic ring, respectively, which can be unsubstituted or substituted with one or more residues, which are preferably selected from among hydroxyl, alkoxy, halogen, carboxy, alkoxycarbonyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C8 alkyl, phenyl, thienyl, pyridyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, pyridylsulfonyl, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, thienylcarbonyl, pyridylcarbonyl, and phenylcarbonyl and wherein R16 and R17 might form a 5-7 membered cycle.        
According to the present invention compounds are also preferred according to formula IV, wherein                R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, phenylsulfonylaminomethyl, thienylsulfonylaminomethyl and C1-C6 alkylaminosulfonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR6R7, cyano and nitro, provided that if R1 is different from hydroxyl or hydroxymethyl, then is R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, and C1-C6 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, fluoro, and NR6R7;        R4 is hydrogen, C1-C3 alkylcarbonyl, or C1-C3 alkyl;        R5 is selected from hydrogen, C1-C3 alkyl, which might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, phenyl, C1-C8 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C8 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, phenyl, fluoro, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein each phenyl or thienyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C6 alkoxy, halogen, C1-C6 alkyl, carboxy, NR16R17, cyano and nitro;        R13, R14 and R15 are independently selected from hydrogen, C1-C4 alkyl, C1-C3 haloalkyl, carboxy, NR6R7, phenyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, phenylaminocarbonyl, thienylaminocarbonyl, halogen and nitro, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C4 alkoxy, fluoro and phenyl; wherein two of these residues selected from R13, R14 and R15 might form a 5-7 membered non-aromatic or aromatic ring;        and wherein phenyl or thienyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C4 alkoxy, halogen, carboxy, C1-C4 alkoxycarbonyl, NR6R7, cyano and nitro; wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkylsulfonyl, phenylsulfonyl, thienylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aminocarbonyl, C1-C6 alkylaminocarbonyl, phenylcarbonyl, and thienylcarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Especially preferred are compounds according to formula IV, wherein                R1 and R2 are selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, cyano, nitro, sulfamoyl, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C1-C4 alkylaminocarbonyl, morpholinocarbonyl, 2-thienylsulfonylaminomethyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7; and wherein the thienyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR6R7 and cyano, provided that if R1 is different from hydroxyl or hydroxymethyl, then R2 must represent hydroxyl or hydroxymethyl;        R3 is selected from hydrogen, halogen, hydroxyl, carboxy, carbamoyl, sulfamoyl, cyano, nitro, NR6R7, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyl, and C1-C3 alkoxycarbonyl, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro, and NR6R7;        R4 is hydrogen or methyl;        R5 is selected from hydrogen and methyl, wherein methyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, methoxy, ethoxy, fluoro, and NR6R7;        R6 and R7 are independently selected from hydrogen, C1-C3 alkyl, C1-C8 alkylsulfonyl, 2-thienylsulfonyl, C1-C8 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C8 alkylaminocarbonyl; wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, carboxy, and NR16R17; and wherein R6 and R7 might form a 5-7 membered cycle; and wherein the thienyl might be unsubstituted or substituted with one or more residues selected from among hydroxyl, C1-C3 alkoxy, halogen, C1-C3 alkyl, carboxy, NR16R17 and cyano;        R13, R14 and R15 are independently selected from hydrogen, C1-C3 alkyl, CF3, carboxy, NR6R7, phenyl, hydroxyl, C1-C3 alkoxy, C1-C3 alkoxycarbonyl, phenylaminocarbonyl, halogen and nitro, wherein each alkyl might be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, fluoro and phenyl;        and wherein phenyl can be unsubstituted or substituted with one or more residues preferably selected from among hydroxyl, C1-C3 alkoxy, halogen, carboxy, C1-C3 alkoxycarbonyl, NR6R7 and cyano; wherein two of these residues might form a 5-7 membered non-aromatic ring.        R16 and R17 are independently selected from among hydrogen, C1-C3 alkyl, C1-C4 alkylsulfonyl, 2-thienylsulfonyl C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, aminocarbonyl, and C1-C4 alkylaminocarbonyl wherein R16 and R17 might form a 5-7 membered cycle.        
Another especially preferred embodiment of the present invention are compounds to according to formula IV, wherein                R1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, carboxy, and methoxymethyl;        R2 is selected from hydrogen, hydroxyl, methoxycarbonyl, carboxy, and hydroxymethyl;        R3 is selected from hydrogen, halogen, methyl, ethyl, methoxycarbonyl, ethoxycarbonyl, carboxy, hydroxymethyl;        R4 is hydrogen or methyl;        R5 is hydrogen or methyl;        R13 is hydrogen or methyl;        R14 is hydrogen        R15 is hydrogen or methyl;        
Most preferred are compounds of formula I to IV, wherein R1 is hydroxyl or hydroxymethyl.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R1 is hydroxyl or hydroxymethyl, and R2 is hydroxyl or hydrogen.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R2 is hydroxyl.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R2 is hydroxyl and R1 is hydroxymethyl, hydroxyl or hydrogen.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R4 is hydrogen.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R5 is hydrogen.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein R1 is hydrogen, hydroxyl or hydroxymethyl, R2 is hydroxyl, and R4 and R5 are both hydrogen.
Further most preferred compounds according to the present invention are compounds according to formula I, wherein the dotted bond represents a double bond.
Further most preferred compounds according to the present invention are compounds according to formula I to IV, wherein the doffed bond represents a double bond.
Further most preferred compounds according to the present invention are compounds according to formula I and the pharmaceutically acceptable salts or solvates thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, selected from the group comprising    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    (R)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    (S)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(3-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol    4-(3-((1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    2-hydroxy-5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoic acid    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    3-(2-Hydroxy-3-(1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino)-propoxy)-phenol    Methyl 2-hydroxy-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    3-Ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    2-Ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    Ethyl 5-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-3-(hydroxymethyl)phenol    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethylphenol    4-(3-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol    1-(4-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(methyl(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(methyl(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)propan-2-ol    1-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-3-(3-(hydroxymethyl)phenoxy)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    4-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoic acid    Methyl 4-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(methoxymethyl)phenol    4-(2-hydroxy-3-(1-(5-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-4-yl piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    4-(3-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-2-hydroxypropoxy)-2-(hydroxymethyl)phenol    1-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-3-(4-(hydroxymethyl)phenoxy)propan-2-ol    2,3-difluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzene-1,2-diol    3-fluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    3-(3-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol    1-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-3-(3-(hydroxymethyl)phenoxy)propan-2-ol
Further most preferred compounds according to the present invention are compounds according to formulas II and 111, and the pharmaceutically acceptable salts or solvates thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, selected from the group comprising:    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    (R)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    (S)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(3-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol    4-(3-((1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    2-hydroxy-5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoic acid    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-ylpiperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    3-(2-Hydroxy-3-(1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino)-propoxy)-phenol    Methyl 2-hydroxy-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    5-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    3-Ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    2-Ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    Ethyl 5-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-3-(hydroxymethyl)phenol    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    Ethyl 2-hydroxy-5-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    1-(4-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(methyl(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(methyl(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)propan-2-ol    1-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-3-(3-(hydroxymethyl)phenoxy)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    1-(3-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol    4-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoic acid    Methyl 4-hydroxy-2-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzoate    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(methoxymethyl)phenol    4-(2-hydroxy-3-(1-(5-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol    1-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-3-(4-(hydroxymethyl)phenoxy)propan-2-ol    2,3-difluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzene-1,2-diol    3-fluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol
Especially preferred compounds according to the present invention are compounds according to formula I-IV and the pharmaceutically acceptable salts or solvates thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, selected from the group comprising    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    (S)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    4-(3-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    2-ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-3-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    1-(4-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(methoxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(3-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-2-hydroxypropoxy)-2-(hydroxymethyl)phenol;    3-(2-Hydroxy-3-(1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino)-propoxy)-phenol    2,3-difluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzene-1,2-diol    3-fluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    3-(3-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol    1-(1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-ylamino)-3-(3-(hydroxymethyl)phenoxy)propan-2-ol
Especially preferred compounds according to the present invention are compounds according to formulas II and III, and the pharmaceutically acceptable salts or solvates thereof, in the form of a racemate or as a substantially pure enantiomer or diastereomer or mixtures of the optical isomers, selected from the group comprising:    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    (S)-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    4-(3-(1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)-2-hydroxypropoxy)phenol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    2-ethyl-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-3-(hydroxymethyl)phenol;    4-(2-hydroxy-3-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    1-(4-(hydroxymethyl)phenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol;    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(methoxymethyl)phenol;    4-(2-hydroxy-3-(1-(5-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)-2-(hydroxymethyl)phenol;    3-(2-Hydroxy-3-(1-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamino)-propoxy)-phenol    2,3-difluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol    4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)benzene-1,2-diol    3-fluoro-4-(2-hydroxy-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propoxy)phenol
One representative example out of the above mentioned compounds was tested in a to binding assay on tachykinin NK1, NK2 and NK3 receptors at a compound concentration of 10 μM and displayed inhibitions which would correlate into IC50 values of around or above 10 μM on each receptor. Comparing these affinities with those described in WO2004014850, compounds of the invention do not show sufficient affinity to qualify as NK1 ligands. Binding assays for affinity at tachykinin receptors NK1, NK2 and NK3 were performed at MDS Pharma Services (Bothell, USA), methods have been adapted from the following scientific literature:    NK1 (Catalog No. 255510) and NK2 (Catalog No. 255600): R. Patacchini et al., Arch. Int. Pharmacodyn. 1995, 329, 161.    NK3 (Catalog No. 255710): J. E. Krause et al., Proc. Natl. Acad. Sci. USA 1997, 94, 310; S. Sadowski et al., Neuropeptides 1993, 24, 317.
Another subject of the present invention is the use of the compounds according to the present invention as a medicament.
Another subject of the present invention is a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable excipient.
A further subject of the present invention is the use of a compound according to the present invention for the preparation of a medicament for the treatment of a disease that is associated with the decreased activation and/or expression of adrenergic beta 3 receptors.
In another embodiment of the invention, a further subject of the present invention is the use of a compound according to the present invention for the preparation of a medicament for the treatment of a disease that is associated with modification of β3 adrenoceptor activity and/or expression.
A preferred subject of the present invention is the use of a compound according to the present invention for the preparation of a medicament for the treatment of an urinary tract disorder, the treatment of a gastrointestinal disorder, the prevention or treatment of dysmenorrhea, the induction and/or enhancement of tocolysis, or the treatment of depression or anxiety disorders.
Especially preferred is the use of any of the compounds according to the present invention, wherein the disorder is urinary incontinence.
Especially preferred is also the use of any of the compounds according to the present invention, wherein the disorder is urinary stress incontinence.
Especially preferred is further the use of any of the compounds according to the present invention, wherein the disorder is urinary urge incontinence.
Especially preferred is further the use of any of the compounds according to the present invention, for the preparation of a medicament for the treatment of obesity or diabetes.
Subject of the present invention is further a method of treating a patient suffering from a disease that improves on stimulation of the adrenergic beta 3 receptor, said method comprising the administration of a compound according to the present invention to said patient.
A preferred subject of the present invention is a method of treating a patient suffering from obesity, diabetes and/or incontinence, said method comprising the administration of a therapeutically effective amount of a compound according to the present invention to said patient.
β3-adrenoceptor agonists of the aryloxypropanolamine scaffold which combine high functional potency and decent selectivity over β1- and β2-adrenoceptors are still rare and thus required. Compounds according to the present invention exhibit high functional potency and decent selectivity over β1- and β2-adrenoceptors.
Alternatively, compounds according to the present invention exhibit high functional potency or decent selectivity over β1- and β2-adrenoceptors.
Preferred are compounds according to the present invention having an EC50(β3)≦100 nM.
Also preferred are compounds according to the present invention having a selectivity of A×B>100. Selectivity has been defined as outlined below.
Most preferred are compounds according to the present invention with EC50(β3)≦100 nM and selectivity A×B>100.
Further most preferred compounds according to the present invention exhibit EC50(β3)≦10 nM.
Further most preferred are compounds with EC50(β3)≦10 nM and selectivity A×B>100.    Another subject of the present invention is a method for producing a compound according to the present invention, comprising the steps            1) treatment of a phenol derivative with a methylene oxirane derivative selected from the group comprising epibromohydrin, epichlorohydrin and glycidyl tosylate under basic conditions        2) treatment of a chloropyrimidine derivative with an amine        3) nucleophilic ring opening of the oxirane as obtained by step (1) with the amine as obtained by step (2),        wherein the order of steps 1 or 2 is interchangeable.        A person skilled in the art would understand that these reaction steps might require incorporation of a protective group strategy for certain building blocks.        
The present invention further comprises a method of producing a compound according to the present invention characterized by the following steps:
Decisive procedure for the construction of compounds has been the nucleophilic ring opening of an oxirane with amines simply by heating the reactants in an appropriate solvent. Aryloxymethyloxiranes themselves were usually generated by treatment of an appropriately substituted and/or protected phenol derivative with either epibromohydrine and an alkali carbonate or sodium hydride and glycidyl tosylate. The amine required for ring opening was prepared from chloropyrimidine derivatives, which were coupled with a protected aminopiperidine in ethyleneglycol under elevated temperature, followed by amine liberation by removal of the protective group. Final synthetic steps included removal of protective groups and/or functional group transformations. References of literature procedures are given below along with synthetic standard protocols.